1. Field of the Invention
Compounds are provided that interfere with c-Myc activity along with uses for the compounds and formulations containing the compounds. Also described is a high-throughput method for screening for drugs that interfere with c-Myc activity.
2. Description of the Related Art
Members of the Myc oncoprotein family, which includes c-Myc, N-Myc, and L-Myc, are frequently deregulated in human cancers. In addition to their transforming properties, these proteins may contribute to the neoplastic phenotype by inhibiting differentiation, reducing growth factor requirements, inducing genomic instability, and promoting angiogenesis. Myc proteins are basic helix-loop-helix-leucine zipper (bHLH-ZIP) transcription factors whose known biological activities require that they heterodimerize with the bHLH-ZIP protein Max (B. Lüscher, L-G. Larsson (1999), Oncogene 18:2995). Mostly as a result of DNA microarray analyses, a large number of positive and negative transcriptional targets for c-Myc have now been identified. Many of these encode proteins that participate in cell growth and metabolism, apoptosis, and extracellular matrix formation, and a number of these are also transforming in their own right. Such functional redundancy suggests that therapies based on the specific inhibition of individual Myc target gene products may be difficult to attain. Rather, the specific inhibition of c-Myc itself may be a more viable alternative.
Previous attempts to inhibit c-Myc function have utilized approaches such as antisense oligonucleotides or gene transfer of Mad family member proteins, which are HLH-ZIP partners of Max that negatively regulate c-Myc. These approaches have had some limited experimental success, but suffer from both theoretical and practical limitations.
As an example of the role c-Myc plays in many cancers, several independent lines of evidence suggest a role for c-Myc in the causation of prostate cancer. Jenkins et al. (Jenkins, R. B., et al. (1997), Cancer Res., 57:524–31.) used FISH and immunocytochemistry to evaluate the status and expression of c-Myc in 48 matched samples of high-grade prostatic intraepithelial neoplasia (PIN) (48 foci), localized prostatic carcinoma (71 foci), and metastases (23 foci). Large increases in c-Myc copy number relative to the chromosome 8 centromere, and concurrent increases in c-Myc immunoreactivity, were observed in 0%, 8% and 21% of foci of PIN, carcinoma, and metastases, respectively. Significant intratumoral molecular heterogeneity was also observed, suggesting the independent and simultaneous evolution of tumor cells within an otherwise histologically uniform focus. A more recent report using both FISH and comparative genomic hybridization (CGH) has provided confirmation for some of these findings by demonstrating >3-fold amplification of c-Myc in 29% of prostatic carcinomas. Several other studies have found similarly high levels of c-Myc amplification.
Mad bHLH-ZIP family members antagonize Myc function and are thus potential tumor suppressors (Luscher, B. and L. G. Larsson (1999)). Mxi1, one of the members of this family, has been mapped to 10q25, a region that is commonly deleted in prostate cancer (Shapiro, D. N., et al. (1994), Genomics, 23:282–5). Evidence is presented for deletion and inactivation of Mxi1 in approximately one-half of primary prostate cancers (Eagle, L. R., et al. (1995), Nat Genet., 9:249–55 and Prochownik, E. V., et al. (1998), Genes Chromosomes Cancer, 22:295–304). Subsequent work has shown that Mxi1 −/− mice develop prostatic dysplasia (Schreiber-Agus, N., et al., (1998), Nature, 393:483–7).